[(1R)-1-[[(2S,3R)-3-hydroxy-2-[6-phenyl-pyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutylboronic acid (Compound 1) is a reversible proteasome inhibitor in the peptide boronic acid class, which may be useful in the treatment of multiple myeloma. Compound 1 and analogs thereof are described in U.S. Pat. No. 7,576,206 (the '206 patent). The chemical structure of Compound 1 is provided below.

Compound 1 is challenging to work with from a pharmaceutical perspective. First, it is obtained in only about 25% yield in four steps from the chiral pinanediol derivative, (1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine
when synthesized according to the method described in the '206 patent, and only one of the prepared intermediates is crystalline. Second, Compound 1 is non-crystalline and hygroscopic, which presents purification and handling issues. For example, chromatographic purification of the Compound 1 obtained from the method of the '206 patent results in a purity of only 96-98%. Third, the immediate precursor to Compound 1 in method of the '206 patent is the pinanediol boronic ester derivative of Compound 1, which is obtained as a non-crystalline glassy foam, and only with difficulty and inefficiency can its diastereomeric purity be improved by chromatography. Therefore, the chiral pinanediol derivative starting material used to prepare the immediate precursor to Compound 1 must be prepared with high chiral purity, and the subsequent reactions must be rigorously controlled to avoid chiral scrambling, which are difficult tasks. Fourth, Compound 1 is unstable and subject to degradation upon exposure to air and/or light, with some batches degrading when stored at temperatures as low as 5° C. For that reason, the standard storage temperature for Compound 1 is −20° C. Fifth, Compound 1 has an occupational exposure limit (OEL) of only 0.3 μg/m3, and therefore requires rigorous, expensive controls during manufacturing to prevent personnel exposure.
Bortezomib ([(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino) butyl]boronic acid; marketed by Millennium Pharmaceuticals under the trade name Velcade®) is also a reversible proteasome inhibitor in the peptide boronic acid class, which is useful in the treatment of multiple myeloma. The chemical structure of bortezomib is provided below.

Bortezomib is also challenging to work with from a pharmaceutical perspective. Perhaps the biggest challenge is that in the syntheses described in U.S. Pat. No. 5,780,454 and U.S. Patent Application No. 2005/0240047, the diastereomeric purity of the bortezomib obtained is almost completely dependent upon the diastereomeric purity of the immediate precursor to bortezomib in the synthetic process. The immediate precursor is the pinanediol boronic ester derivative of bortezomib, which is a non-crystalline glassy foam that is difficult and inefficient to purify by chromatography.
Improved methods for preparing and purifying Compound 1 and bortezomib are required. Also required are high purity and storage stable forms of Compound 1.